For hereditary enzyme deficiency, for which no radical treatments have been known to date, enzyme replacement therapy in which an enzyme is produced by genetic engineering and then administered to the blood vessel by intravenous drip or the like has been gradually developed. As an example of hereditary enzyme deficiency whose prevalence is relatively high and which is designated as a specified disease (intractable disease), Fabry disease (hereditary α-galactosidase deficiency, also called lysosomal disease, which is one of the genetic diseases), is well known (see Kenneth J. Dean et al., Fabry Disease, “Practical Enzymology of the Sphingolipidoses”, U.S.A., Aln R. Liss, Inc., 1997, p. 173-216).
Fabry disease is a glycolipid metabolic disorder which develops as follows: As a result of a decrease in the activity or deficiency of an enzyme called “α-galactosidase” present in a lysosome, one of the human intracellular organelles, a glycolipid called globotriaosylceramide (GL-3; also referred to as ceramide trihexoside (CTH)), which is an in vivo substrate of the enzyme, is not degraded and thus accumulated within the body (for example, the blood vessels, skins, cornea, nerves, kidneys, and heart).
Since a gene encoding α-galactosidase lies on the X chromosome, this disease has an X-chromosomal mode inheritance. Therefore, in this disease, a definite clinical feature is displayed mainly in hemizygous males. It is believed that “classic Fabry disease”, which takes a typical clinical course, develops in about one out of 40,000 male children. Symptoms such as pain in the hand and the foot, hypohidrosis, angiokeratoma, and corneal opacity appear during the childhood and adolescence; these symptoms progress and then cause systemic organ damage such as renal failure, heart failure, and cerebrovascular disorder in middle age or later, which become a cause of death. There is also “variant Fabry disease”, which does not take such a typical clinical course as “classic Fabry disease” and which develops late and takes a relatively moderate course. In patients with this type of disease, remaining α-galactosidase activity is observed though it is low. As a variant Fabry disease, for example, “cardiac Fabry disease” is known, which causes the above-mentioned glycolipid accumulation mainly in the heart. Consequently, cardiac hypertrophy occurs, and disorders such as heart failure and arrhythmia are caused. On the other hand, in heterozygous female Fabry disease patients, various types of clinical features are observed in accordance with the characteristics of the X chromosome. Specifically, cases range from serious cases which are similar to those of hemizygous males to cases in which substantially no symptoms are observed. However, according to recent research, it has become clear that most heterozygous female Fabry disease patients develop some sort of symptoms with age. There is a viewpoint that they should not be regarded as “carriers” but as “patients”.
Recently, enzyme replacement therapy has been established for Fabry disease as well, and a recombinant human α-galactosidase produced in a cell derived from mammals has been used widely as an active element of a Fabry disease therapeutic agent in the above therapy (see Eng C M et al., Am J Hum Genet, 68: 711-722 (2001); Eng C M et al., N Engl J Med, 345: 9-16 (2001); and Schiffmann R et al., Proc Natl Acad Sci USA, 97: 365-370 (2000)).
There have also been proposed a method in which a recombinant human α-galactosidase produced with a non-animal cell (for example, yeast) as a host may be used for the treatment of Fabry disease (enzyme replacement therapy) (see Japanese Unexamined Patent Application Publication No. 2002-369692), a gene therapeutic method in which an enzyme is replaced by introducing a gene encoding human α-galactosidase into a cell of an affected tissue to express the gene (see Japanese Unexamined Patent Application Publication (Translation of PCT Application) No. 2002-522509), and the like.